Cyclic AMP-dependent positive feedback signaling pathways in the cortex contributes to visceral pain
Cyclic AMP-dependent positive feedback signaling pathways in the cortex contributes to visceral pain
复制标题
皮质中环磷酸腺苷依赖性正反馈信号通路导致内脏疼痛
DOI：
10.1111/jnc.14903
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发表时间：
2020-02-09
影响因子：
4.7
通讯作者：
Zhuo, Min
中科院分区：
文献类型：
--
作者：
Liu, Shui-bing;Wang, Xin-shang;Zhuo, Min
包括扣带回前皮质(ACC)在内的皮质区域在不同类型的慢性疼痛中起着关键作用。以前的研究大多集中在躯体区域的感觉输入，而关于内脏疼痛的皮质可塑性变化的信息较少。本研究采用成年雄性C57/BL6小鼠结肠内注射酵母多糖的方法建立慢性内脏痛动物模型。采用全细胞膜片钳记录、行为学测试、免疫印迹、插管和ACC微量注射等方法，探讨腺酰环化酶1(AC1)在C57/BL6和AC1基因敲除小鼠ACC中的作用。采用综合方法研究损伤后ACC内神经元AC1的变化。我们发现，在肠易激综合征的动物模型中，AC1，一种与疼痛相关的皮质可塑性的关键酶，在ACC中显著增加。选择性AC1抑制剂NB001抑制AC1活性可显著降低AC1蛋白在ACC中的上调。此外，我们发现AC1是NMDA GluN2B受体上调和NMDA受体介导的电流增加所必需的。这些结果提示，在慢性内脏痛时，AC1可能在大脑皮层形成一种正向调节。我们的研究结果表明，皮层AC1蛋白的上调可能是慢性内脏痛的病理基础；抑制AC1的活性可能有利于内脏痛的治疗。
Cortical areas including the anterior cingulate cortex (ACC) play critical roles in different types of chronic pain. Most of previous studies focus on the sensory inputs from somatic areas, and less information about plastic changes in the cortex for visceral pain. In this study, chronic visceral pain animal model was established by injection with zymosan into the colon of adult male C57/BL6 mice. Whole cell patch-clamp recording, behavioral tests, western blot, and Cannulation and ACC microinjection were employed to explore the role of adenylyl cyclase 1 (AC1) in the ACC of C57/BL6 and AC1 knock out mice. Integrative approaches were used to investigate possible changes of neuronal AC1 in the ACC after the injury. We found that AC1, a key enzyme for pain-related cortical plasticity, was significantly increased in the ACC in an animal model of irritable bowel syndrome. Inhibiting AC1 activity by a selective AC1 inhibitor NB001 significantly reduced the up-regulation of AC1 protein in the ACC. Furthermore, we found that AC1 is required for NMDA GluN2B receptor up-regulation and increases of NMDA receptor-mediated currents. These results suggest that AC1 may form a positive regulation in the cortex during chronic visceral pain. Our findings demonstrate that the up-regulation of AC1 protein in the cortex may underlie the pathology of chronic visceral pain; and inhibiting AC1 activity may be beneficial for the treatment of visceral pain.